Pharmaceutical spray composition comprising a vitamin D analogue and a corticosteroid

ABSTRACT

The present invention relates to a topical spray composition comprising a biologically active vitamin D derivative or analog and a corticosteroid, and its use in the treatment of dermal diseases and conditions.

CROSS REFERENCE

The present application is a 37 C.F.R. § 1.53(b) continuation of, andclaims priority to, U.S. application Ser. No. 13/703,214, filed Jan. 28,2013. Application Ser. No. 13/703,214 is the national phase under 35U.S.C. § 371 of International Application No. PCT/DK2011/000060, filedon Jun. 10, 2011, which claims priority under 35 USC 119(e) to U.S.Provisional Application No. 61/353,893 filed on Jun. 11, 2010. Theentire contents of each of these applications is hereby incorporated byreference.

FIELD OF INVENTION

The present invention relates to a topical spray composition comprisinga biologically active vitamin D derivative or analogue and acorticosteroid, and its use in the treatment of dermal diseases andconditions.

BACKGROUND OF THE INVENTION

Psoriasis is a chronic inflammatory skin disease that manifests aserythematous, dry, scaling plaques resulting from hyperkeratosis. Theplaques are most often found on the elbows, knees and scalp, though moreextensive lesions may appear on other parts of the body, notably thelumbosacral region. The most common treatment of mild to moderatepsoriasis involves topical application of a composition containing acorticosteroid as the active ingredient. While efficacious, applicationof corticosteroids has the disadvantage of a number of adverse effectssuch as skin atrophy, striae, acneiform eruptions, perioral dermatitis,overgrowth of skin fungus and bacteria, hypopigmentation of pigmentedskin and rosacea.

For many years, however, an advantageous non-steroidal treatment ofpsoriasis has consisted in topical treatment with the vitamin D analoguecompound, calcipotriol, formulated in an ointment composition (marketedas Daivonex® or Dovonex® ointment by LEO Pharma) in which thecalcipotriol is present in solution or a cream composition (marketed asDaivonex® or Dovonex® cream by LEO Pharma). The solvent in the ointmentcomposition is propylene glycol which has the advantage of enhancingpenetration of the active ingredient into the skin, leading to animproved efficacy, but which is also known to act as a skin irritant.Thus, it has been reported that the inclusion of propylene glycol intopical compositions frequently causes patients to develop contactdermatitis (one study reported a number of irritant reactions topropylene glycol of 12.5%, cf. M. Hannuksela et al., Contact Dermatitis1, 1975, pp. 112-116), and the number of irritant reactions increaseswhen propylene glycol is used in high concentrations (as reviewed by J.Catanzaro and J. Graham Smith, J. Am. Acad. Dermatol. 24, 1991, pp.90-95). Due to the improved penetration of calcipotriol into the skinresulting, inter alia, from the presence of propylene glycol, Daivonex®ointment has been found to be more efficacious in the treatment ofpsoriatic lesions than Daivonex® cream, but has also caused skinirritation in a significant proportion of psoriasis patients.

More recently, a combination product for the treatment of psoriasis hasbeen marketed by LEO Pharma under the trade name Daivobet® ointment. Theproduct comprises calcipotriol and betamethasone dipropionate as theactive ingredients formulated in an ointment composition in whichcalcipotriol is dissolved in polyoxypropylene-15-stearyl ether andbetamethasone dipropionate is present as a suspension. While theefficacy of the combination is significantly superior to that of eitheractive ingredient on its own, the ointment may be perceived ascumbersome to apply as it requires prolonged rubbing into the skin ofthe affected area, and many patients, in particular those with extensivepsoriatic lesions would favour a greater ease of application such as isprovided by a spray composition. Daivobet® ointment does not contain anypenetration enhancer such as propylene glycol which has been found to bedetrimental to the chemical stability of calcipotriol (cf. example 2 ofWO 00/64450). It is considered desirable to further improve thebiological efficacy of the combination of the two active ingredients byproviding a formulation vehicle from which penetration of the activeingredients into the skin is improved compared to the commercialproduct.

WO 00/64450 dicloses a pharmaceutical composition comprising a vitamin Danalogue and a corticosteroid formulated in a solvent containing vehiclein which both active ingredients are chemically stable. The preferredembodiment of the composition is an ointment and there is no mention ofproviding a spray composition with improved properties compared to anointment.

US 2005/0281749 discloses a spray composition comprising acorticosteroid and a vitamin D derivative solubilised in an oily phasecomposed of one or more oils. The oil may be selected from a vegetable,mineral, animal, synthetic or silicone oil. There is no suggestion thatit might be desirable to provide occlusion and consequently it is notproposed to add a semi-solid and occlusive excipient to the composition.There is no indication whether the composition exhibits improvedpenetration properties.

US 2005/0281754 discloses a spray composition comprising acorticosteroid and a vitamin D derivative formulated in a vehiclecomprising an alcohol phase and an oil phase. The alcohol phase iscomposed of for instance ethanol, isopropanol or butanol. The oil phasemay be composed of a mineral, vegetable or synthetic oil. There is nosuggestion of including a semi-solid and occlusive excipient to thecomposition, and no indication whether the composition exhibits improvedpenetration properties.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a topical spray compositioncomprising a vitamin D derivative or analogue and a corticosteroid asthe active ingredients, which has skin penetration and biologicalactivity properties superior to those of Daivobet® ointment but whichcontains a solvent for the active ingredients that unlike propyleneglycol is not detrimental to the chemical stability of either thevitamin D derivative or analogue or the corticosteroid.

Human skin, in particular the outer layer, the stratum corneum, providesan effective barrier against penetration of microbial pathogens andtoxic chemicals. While this property of skin is generally beneficial, itcomplicates the dermal administration of pharmaceuticals in that a largequantity, if not most, of the active ingredient applied on the skin of apatient suffering from a dermal disease may not penetrate into theviable layers of the skin where it exerts its activity. To ensure anadequate penetration of the active ingredient to the dermis andepidermis, it is generally preferred to include the active ingredient ina dissolved state, typically in the presence of a solvent in the form ofan alcohol, e.g. ethanol, or diol, e.g. propylene glycol. Propyleneglycol is a well-known penetration enhancer, i.e. a substance which iscapable of penetrating the stratum corneum and “draw” low-molecularcomponents such as therapeutically active components in the vehicle intothe epidermis. Propylene glycol may in itself give rise to significantskin irritation, and it is also capable of “drawing” low-molecular andpotentially irritative components of the vehicle into the epidermis,leading to an overall irritative effect of conventional vehiclesincluding propylene glycol. For this reason, the presence of propyleneglycol as a solvent in compositions intended for the treatment ofinflammatory skin diseases may exacerbate the inflammatory response.

Another object of the invention is to provide a composition withimproved penetration and biological activity of the active ingredientscompared to Daivobet® ointment in the absence of conventionalpenetration enhancers such as propylene glycol which are detrimental tothe stability of vitamin D compounds such as calcipotriol.

A further object of the invention is to provide a composition in whichboth the vitamin D derivative or analogue and the corticosteroid willnot be significantly degraded. It is well known, e.g. from WO 00/64450that vitamin D compounds are chemically unstable in acidic environmentsor in the presence of acid reacting components or impurities in theformulation vehicle. Likewise, it is well known that corticosteroids arechemically unstable in alkaline environments or in the presence ofalkali reacting components or impurities in the formulation vehicle. Ina composition comprising both ingredients the problem of chemicalinstability may not readily be solved by adding an acid or alkalineutralizing agent, respectively. On the contrary, care must be taken inthe selection of excipients for inclusion in the composition such thatno components are included which are detrimental to the chemicalstability of either active ingredient.

Unlike the spray compositions disclosed in the references cited above,it is an object of the invention to provide a spray composition whichcontains significant amounts of an occlusive and semi-solid carrierexcipient as the known oily spray formulations are more likely to spreadto non-affected areas on application, whereas the semi-solid componentmakes the present composition less “runny” such that the activeingredients are preferentially applied on affected skin areas.

Thus, in one aspect the invention relates to a sprayable, storagestable, substantially anhydrous topical composition comprising atherapeutically effective amount of a vitamin D derivative or analogueand a therapeutically effective amount of a corticosteroid, the vitaminD derivative or analogue and the corticosteroid being dissolved in apharmaceutically acceptable propellant selected from the groupconsisting of dimethyl ether, diethyl ether and methylethyl ether or apropellant mixture comprising a first propellant selected from the groupconsisting of dimethyl ether, diethyl ether and methylethyl ether and asecond propellant selected from the group consisting of C₃₋₅ alkanes,hydrofluoroalkanes, hydrochloroalkanes, fluoroalkanes andchlorofluoroalkanes the composition further comprising apharmaceutically acceptable lipid carrier solubilized or suspended insaid propellant or propellant mixture, the lipid carrier comprising oneor more lipids which on application on skin and evaporation of thepropellant form a semi-solid and occlusive layer at the site ofapplication.

The composition of the invention was surprisingly found to facilitateimproved peneration of the active ingredients compared to the commercialDaivobet® ointment even in the absence of a conventional penetrationenhancer. It is currently believed that improved penetration may be theresult of the formation of a supersaturated solution of the activeingredients on the skin after application and evaporation of thepropellant or propellant mixture (cf. Reid et al., Pharm. Res. 25(11),2008, pp. 2573-2580). It is further believed that the propellant(s)themselves may act as penetration enhancers driving the activeingredients into the skin. Finally, the formation of a semi-solid andocclusive layer at the site of application may contribute to thepenetration of the active ingredients.

In another aspect, the invention relates to a composition as disclosedherein for use in the treatment of dermatological diseases orconditions.

The compositions according to the invention may be dispensed fromaerosol containers, typically of the type comprising a container bodyand valve assembly. The container body may, for instance, comprise ametal body, preferably lined with an chemically inert coating materialto avoid degradation of the composition due to interaction between thebody and the composition.

The valve assembly may comprise a valve cup, sometimes referred to as amounting cup, a valve body or housing provided with a valve stem, aspring, a dip tube and an actuator. An inner gasket typically seals ahole in the valve stem, but when the actuator is operated the valve stemis shifted so that the hole is uncovered. Once exposed, the pressureexerted by the propellant in the container body forces the compositionto flow through the hole into the dip tube and the valve stem and outthrough the actuator. As will be understood, when the actuator isreleased the valve spring returns the valve stem to the position wherethe hole is once again sealed.

The valve stem and actuator each contain one or more holes (orifices)and channels, the number, size and shape of which are determined inconjunction with the physical properties of the particular compositionformulation so as to control both the flow rate through the valve andthe characteristics of the spray that emerges from the actuator.

The spray pattern and flow rate may be controlled by means of a separateinsert fitted into the outlet orifice of the actuator and which providesthe terminal orifice for the actuator assembly. The channel through theinsert leading to the outlet typically includes a portion narrower indiameter than the channel in the body of the actuator so that fluidemerging from the actuator channel into the insert channel is caused toswirl and break up into droplets. The insert may be profiled, forexample it may be stepped, so that the composition is forced forwardsand out of the terminal orifice in a forward motion, rather than themore usual rotational motion. This results in a homogeneous or solidspray pattern and hence enabling a user better to focus the compositionon the area of skin being treated.

Since inhalation of the composition according to the invention is notdesirable, it is preferred that the dimensions of the fluid channels,orifices, inserts, etc are selected to avoid production of a fine miston expulsion.

The valve assembly may comprise a metering valve to permit only ametered quantity of the composition to be dispensed with each actuationof the actuator.

For storage, safety and/or hygiene reasons, the actuator may be providedwith an protective hood or overcap, separate or integral therewith. Theovercap may be moveable from a first position in which the terminalorifice is enclosed to a second position where the orifice is exposed;in the second position, the cover may also function as a directingnozzle by limiting the spray area. The actuator itself may comprise asimple button actuator, or may for example comprise a flip-top ortwist-lock. In another arrangement, an overcap having an integral fingeractuator may be secured to the container and cover an underlyingactuator button. The underside of the overcap may include for example aplurality of projections for contacting the actuator button uponmovement due to finger pressure of the operator and triggering the valveto open.

Alternatively, or in addition thereto, the actuator may be moveablebetween a first position in which the valve is prevented from beingintentionally or accidentally operated and a second operative position.For example, part of the valve assembly may be rotatable about the valvestem such that in one rotary position the actuator is operable todispense the product while in another rotary position the actuatoraligns with projections or abutments on the container to preventactuation. Such a “twist and spray” mechanism may include tactile oraudible indications of the open and closed positions.

The inclusion of a tamper-evidence tab, which has to be broken beforefirst use of the aerosol container, is desirable.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a and 1b are graphs showing the solubility of calcipotriol in100% dimethyl ether (DME) and in different ratios of DME and butane inthe continuous phase (FIG. 1a ) and in the mixture of continuous anddispersed phases (FIG. 1b ).

FIGS. 2a and 2b are graphs showing the solubility of betamethasonedipropionate (BDP) in 100% DME and in different ratios of DME and butanein the continuous phase (FIG. 2a ) and in the mixture of the continuousand dispersed phases (FIG. 2b ).

FIG. 3 is a graph showing the penetration of calcipotriol (MC 903) intoviable skin from Composition E according to the invention at 2, 6 and 21hours after application compared to the penetration of calcipotriol fromDaivobet® ointment similarly applied.

FIG. 4 is a graph showing the penetration of BDP into viable skin fromComposition E according to the invention at 2, 6 and 21 hours afterapplication compared to the penetration of BDP from Daivobet® ointmentsimilarly applied.

FIG. 5 is a schematic representation of the activation of the geneencoding cathelicidin by vitamin D₃ in human keratinocytes. Themechanism of cathelicidin gene activation is used in a biological assayusing reconstructed human epidermis (human keratinocytes cultured so asto form the epidermal layers characteristic of human skin) on whichcalcipotriol-containing compositions of the invention are applied toactivate cathelicidin as described in detail in Example 5 below.

FIG. 6a shows a cross-section of a container intended for a pressurizedspray composition of the invention, comprising a container body (1) ontowhich is fitted a valve assembly comprising a valve cup (3), a valvebody (5), an actuator (4) and a dip tube (2). As shown in thisembodiment, the present composition may be a two-phase system comprisinga composition phase (6) and a vapor phase (8).

FIG. 6b shows a cross-section of a container intended for a pressurizedspray composition of the invention, comprising a container body (1) ontowhich is fitted a valve assembly comprising a valve cup (3), a valvebody (5), an actuator (4) and a dip tube (2). As shown in thisembodiment, the present composition may be a three-phase systemcomprising a vehicle phase (6), a propellant phase (7) and a vapor phase(8).

FIG. 7 shows a cross-section of a valve assembly to be mounted on thebody of a container body (1), comprising a valve cup (3) provided withsealing (31) between the container body (1) and the valve cup (3) and agasket (32), a valve body (5) provided with a valve stem (51) and aspring (53) connected to an actuator (4) provided with an insert (44)with a terminal orifice (41) through which the composition present inthe container body (1) is expelled when the actuator (4) is depressed.The valve stem (51) contains an aperture (52) through which thecomposition present in the container body (1) may flow when the actuatoris depressed. The valve body is further provided with a tailpiece (55)to which the dip tube (2) is connected. The tailpiece (55) is providedwith an aperture (54) permitting the composition to flow from the diptube (2).

DETAILED DISCLOSURE OF THE INVENTION Definitions

The term “vitamin D derivative” is intended to indicate a biologicallyactive metabolite of vitamin D₃, such as calcitriol, or a precursor tosuch a metabolite, such as alfacalcidol.

The term “vitamin D analogue” is intended to indicate a syntheticcompound comprising a vitamin D scaffold with sidechain modificationsand/or modifications of the scaffold itself. The analogue exhibits abiological activity on the vitamin D receptor comparable to that ofnaturally occurring vitamin D compounds.

“Calcipotriol” is a vitamin D analogue of the formula

Calcipotriol has been found to exist in two crystalline forms, ananhydrate and a monohydrate. Calcipotriol monohydrate and itspreparation are disclosed in WO 94/15912.

The term “storage stability” or “storage stable” is intended to indicatethat the composition exhibits chemical and physical stabilitycharacteristics that permit storage of the composition for a sufficientperiod of time at refrigeration or, preferably, room temperature to makethe composition commercially viable, such as at least 12 months, inparticular at least 18 months, and preferably at least 2 years.

The term “chemical stability” or “chemically stable” is intended to meanthat no more than 10%, preferably no more than 6%, of the activeingredients degrades over the shelf-life of the product, typically 2years, at room temperature. An approximation of chemical stability atroom temperature is obtained by subjecting the composition toaccelerated stability studies at 40° C. where the composition is placedin a heating cupboard at 40° C. and samples are taken at 1, 2 and 3months and tested for the presence of degradation products by HPLC. Ifless than about 10% of the substance has degraded after 3 months at 40°C., this is usually taken to correspond to a shelf-life of 2 years atroom temperature. When the active ingredient included in the compositionis calcipotriol, “chemical stability” usually indicates that thecalcipotriol does not degrade significantly over time to 24-epicalcipotriol or other degradation products of calcipotriol in thefinished pharmaceutical product.

The term “physical stability” or “physically stable” is intended to meanthat the active ingredients do not precipitate from the propellant orvehicle phases over the shelf life of the composition.

The term “substantially anhydrous” is intended to mean that the contentof free water in the ointment composition does not exceed about 2% byweight, preferably not about 1% by weight, of the composition.

The term “medium-chain triglycerides” is used to indicate triglycerideesters of fatty acids with a chain length of 6-12 carbon atoms. Acurrently favoured example of such medium chain triglycerides is amixture of caprylic (C₈) and capric (C₁₀) triglycerides, e.g. availableunder the trade name Miglyol 812.

The term “solubilization capacity” is intended to indicate the abilityof a solvent or mixture of solvents to dissolve a given substance,expressed as the amount required to effect complete dissolution of thesubstance.

The term “semi-solid” is used to denote a composition or excipient whichshows viscoelastic behaviour and is non-Newtonian in character, i.e.does not flow at low shear stress, but exhibits plastic, pseudoplasticor thixotropic flow behaviour at high shear rates at room temperature.Typical examples of semi-solid compositions are ointments and creams.

The term “occlusive” is intended to indicate the provision of a lipidlayer on the skin surface which forms a hydration barrier sufficient toresult in reduction of transepidermal water loss, resulting in skinhydration.

The term “skin penetration” is intended to mean the diffusion of theactive ingredient into the different layers of the skin, i.e. thestratum corneum, epidermis and dermis.

The term “skin permeation” is intended to mean the flux of the activeingredient through the skin into the systemic circulation or, in case ofin vitro studies such as those reported in Example 4 below, the receptorfluid of the Franz cell apparatus used in the experiment.

The term “biological activity” is intended to mean the activity of avitamin D derivative or analogue when applied to skin in a compositionof the invention. The biological activity of compositions is determinedin an in vitro assay measuring the activation of a target gene encodingcathelicidin in a reconstructed human epidermis model involving culturedhuman keratinocytes, as described in detail in Example 5 below.

Embodiments of the Invention

The vitamin D derivative or analogue included in the present compositionmay be selected from calcipotriol, calcitriol, tacalcitol, maxacalcitol,paricalcitol and alfacalcidol. A preferred vitamin D analogue which hasbeen shown to be effective in the treatment of psoriasis iscalcipotriol. Before dissolution in the solvent mixture, calcipotriolmay be in the form of anhydrate or monohydrate, preferably themonohydrate.

The corticosteroid included in the present composition may be selectedfrom the group consisting of amcinonide, betamethasone, budenoside,clobetasol, clobetasone, cortisone, desonide, desoxycortisone,desoximethasone, dexamethasone, diflucortolon, diflorasone,flucortisone, flumethasone, flunisolide, fluocinonide, fluocinolon,fluorometholone, fluprednisolone, flurandrenolide, fluticasone,halcinonide, halobetasol, hydrocortisone, meprednisone,methylprednisone, mometasone, paramethasone, prednicarbate, prednisone,prednisolone and triamcinolone or a pharmaceutically acceptable ester oracetonide thereof. The corticosteroid may preferably be selected frombetamethasone, budenoside, clobetasol, clobetasone, desoximethasone,diflucortolon, diflorasone, fluocinonide, fluocinolon, halcinonide,halobetasol, hydrocortisone, mometasone and triamcinolone or apharmaceutically acceptable ester thereof. The corticosteroid ester mayfor instance be betamethasone acetate, betamethasone dipropionate,betamethasone valerate, clobetasol propionate, dexamethasone acetate,flumethasone pivalate, fluticasone propionate, hydrocortisone acetate,hydrocortisone butyrate or mometasone furoate. The acetonide may beselected from fluocinolone acetonide or triamcinolone acetonide.

The composition according to the invention may further comprise anon-evaporating oily co-solvent selected from at least one of thefollowing solvent classes

(a) a compound of general formula IH(OCH₂C(CH₃)H)_(x)OR¹

wherein R¹ is straight or branched chain C₁₋₂₀ alkyl, and x is aninteger of 2-60;

(b) an isopropyl ester of a straight or branched chain C₁₀₋₁₈ alkanoicor alkenoic acid;

(c) a propylene glycol diester of a C₈₋₁₄ alkanoic or alkenoic acid;

(d) a straight or branched C₈₋₂₄ alkanol or alkenol;

(e) highly purified vegetable oils such as medium chain triglycerides orlong chain triglycerides; and

(f) N-alkylpyrrolidone or N-alkylpiperidone.

The oily co-solvent may serve to maintain the solubilization capacity ofthe composition on evaporation of the propellant or propellant mixturesuch that the active ingredients do not crystallize rapidly on the skinon evaporation of the propellant, but are present on the skin as asaturated solution from which they may penetrate into the skin (cf. Reidet al, Pharm. Res. 25 (11), 2008, pp. 2573-2580).

In one embodiment, the oily co-solvent included in the presentcomposition may be a compound of general formula I such aspolyoxypropylene-15-stearyl ether, polyoxypropylene-11-stearyl ether,polyoxypropylene-14-butyl ether, polyoxypropylene-10-cetyl ether orpolyoxypropylene-3-myristyl ether.

In another embodiment, the oily co-solvent may be an isopropyl ester ofa straight or branched chain C₁₀₋₁₈ alkanoic or alkenoic acid such asisopropyl myristate, isopropyl palmitate, isopropyl isostearate,isopropyl linolate or isopropyl monooleate.

In a further embodiment, the oily co-solvent may be a propylene glycoldiester of a C₈₋₁₄ alkanoic acid such as propylene glycol dipelargonate.

In a still further embodiment, the oily co-solvent may be a straightC₈₋₂₄ alkanol, such as capryl, lauryl, cetyl, stearyl, oleyl, linoelylor myristyl alcohol, or a branched C₈₋₂₄ alkanol, preferably C₁₈₋₂₄alkanol, such as 2-octyldodecanol.

In a still further embodiment, the oily co-solvent is N-alkylpyrrolidonesuch as N-methylpyrrolidone.

In the research leading to the present invention, it was surprisinglyfound that using a pure C₃₋₅ alkane such as butane as the propellant didnot lead to sufficient dissolution of the active ingredients so that thevitamin D analogue precipitated out of the solution with time andcrystal growth of the corticosteroid was observed, i.e. the compositionwas not physically stable for the shelf-life of the composition. It wassurprisingly found that this problem did not occur when dimethyl etherwas used as the propellant on its own or even when a proportion ofdimethyl ether was added to the C₃₋₅ alkane to form a propellantmixture. Thus, in a currently preferred embodiment the presentcomposition comprises dimethyl ether as the sole propellant or as thefirst propellant of the propellant mixture.

In the present composition, the second propellant of the propellantmixture is favourably a C₃₋₅ alkane, preferably selected from the groupconsisting of n-propane, isopropane, n-butane or isobutane. Aparticularly favoured C₃₋₅ alkane is n-butane and/or isobutane.

In the propellant mixture, the ratio of n-butane and/or isobutane todimethyl ether may favourably be in the range of 6:1-0:1 v/v, such as5:1-1:2, 4:1-1:1, 4:2-1:1, 4:2-4:3 or 4:3-1:1.

In a particular embodiment, the composition comprises

(a) about 0.00001-0.05% w/w of the vitamin D derivative or analogue,

(b) about 0.0005-1% w/w of the corticosteroid,

(c) about 5-55% w/w of the lipid carrier, and

(d) about 45-95% w/w of the propellant or propellant mixture.

More specifically, the present composition may comprise about 10-50%w/w, about 15-45% w/w, or about 20-40% w/w of the lipid carrier.

More specifically, the present composition may comprise about 50-90% w/wor about 55-70% w/w of the propellant or propellant mixture.

In a specific embodiment, the present composition may further compriseabout 0.1-10% w/w of the oily solvent as defined above, such as about0.5-3% w/w, about 1-2.5% w/w or about 1.5-2% w/w of the oily solvent.

The lipid carrier may be a hydrocarbon or mixture of hydrocarbons withchain lengths ranging from C₅ to C₆₀. A frequently used ointment carrieris petrolatum, or white soft paraffin, which is composed of hydrocarbonsof different chain lengths peaking at about C₄₀₋₄₄, or a mixture ofpetrolatum and liquid paraffin (consisting of hydrocarbons of differentchain lengths peaking at C₂₈₋₄₀). While white soft paraffin providesocclusion of the treated skin surface, reducing transdermal loss ofwater and potentiating the therapeutic effect of the active ingredientin the composition, it tends to have a greasy or tacky feel whichpersists for quite some time after application. It may therefore bepreferred to employ paraffins consisting of hydrocarbons of a somewhatlower chain length, such as paraffins consisting of hydrocarbons withchain lengths peaking at C₁₄₋₁₆, C₁₈₋₂₂, C₂₀₋₂₂, C₂₀₋₂₆ or mixturesthereof. It has been found that such paraffins are more cosmeticallyacceptable in that they are less greasy or tacky on application. Theinclusion of such paraffins in the present composition is thereforeexpected to result in improved patient compliance. Suitable paraffins ofthis type, termed petrolatum jelly, are manufactured by Sonneborn andmarketed under the trade name Sonnecone, e.g. Sonnecone CM, SonneconeDM1, Sonnecone DM2 and Sonnecone HV. These paraffins are furtherdisclosed and characterized in WO 2008/141078 which is incorporatedherein by reference. In addition to their favourable cosmeticproperties, it has surprisingly been found that compositions containingthese paraffins as carriers are more tolerable than compositionscontaining conventional paraffins. (The hydrocarbon composition of theparaffins has been determined by gas chromatography). The lipid carriermay also be an isoparaffin such as isohexadecane.

The present composition may suitably include a lipophilicviscosity-increasing ingredient capable of imparting to the lipidcarrier the property of forming a semi-solid and occlusive layer on skinafter application and evaporation of the propellant. The lipophilicviscosity-increasing ingredient may suitably be a wax such as a mineralwax composed of a mixture of high molecular weight hydrocarbons, e.g.saturated C₃₅₋₇₀ alkanes, such as microcrystalline wax. Alternatively,the wax may be a vegetable or animal wax, e.g. esters of C₁₄₋₃₂ fattyacids and C₁₄₋₃₂ fatty alcohols, such as beeswax, a silicone wax orhydrogenated castor oil, or mixtures thereof. The amount ofviscosity-increasing ingredient may typically be in the range of about0.01-5% by weight of the composition. When the viscosity-increasingingredient is hydrogenated castor oil it is typically present in anamount in the range of about 0.05-1% by weight, e.g. about 0.1-0.5% byweight, of the composition.

The composition may additionally comprise an emollient which may act tosoften the thickened epidermis of the psoriatic plaques. A suitableemollient for inclusion in the present composition may be a volatilesilicone oil as the presence of silicone has additionally been found toaid penetration of calcipotriol into the skin. Compositions including asilicone oil have also been found to result in less skin irritation.Suitable silicone oils for inclusion in the present composition may beselected from cyclomethicone and dimethicone. The amount of silicone oilincluded in the present composition is typically in the range of 0.3-3%w/w, such as about 0.5-1.5% w/w.

The present composition may also comprise other components commonly usedin dermal formulations, e.g. antioxidants (e.g. alpha-tocopherol),preservatives, pigments, skin soothing agents, skin healing agents andskin conditioning agents such as urea, glycerol, allantoin or bisabolol,cf. CTFA Cosmetic Ingredients Handbook, 2^(nd) Ed., 1992. In a favouredembodiment, the composition may comprise an anti-irritative agent suchas menthol, eucalyptol or nicotinamide. A currently preferredanti-irritative agent is menthol as it has been found also to increasethe penetration of calcipotriol into the skin, cf. FIG. 1. The mentholmay be included in the composition in an amount of about 0.001-1% w/w,in particular about 0.002-0.003% w/w, of the composition.

The composition of the invention may be used in the treatment ofpsoriasis, sebopsoriasis, pustulosis palmoplantaris, dermatitis,ichtyosis, rosacea and acne and related skin diseases by topicallyadministering an effective amount of a composition according to theinvention to a patient in need of such treatment. Said method preferablycomprises topical administration once or twice a day of atherapeutically sufficient dosage of said composition. To that end, thecomposition according to the invention preferably contains about0.001-0.5 mg/g, preferably about 0.002-0.25 mg/g, in particular0.005-0.05 mg/g, of the vitamin D derivative or analogue. It isenvisaged that the present composition may advantageously be used formaintenance treatment of these dermal diseases, i.e. continued treatmentafter the disappearance of visible symptoms of the disease in order todelay recurrence of the symptoms.

In a further aspect, the invention relates to a pressurized containeradapted to dispensing a topical composition on an affected skin area,the container comprising a composition according to the invention and avalve assembly and actuator for releasing the composition in the form ofa spray.

As shown in FIGS. 6a and 6b , an example of a container suitable for apressurized product may be composed of a container body (1) in which thepresent composition is stored, a dip tube (2), and a valve assemblycomprising a valve cup (3), a valve body (5) and an actuator (4).

Typically, the container body (1) may be constructed from materials suchas metal, glass, ceramics, polyester, polyethylene terephthalate (PET)or other polymer, or the like. Glass containers may be provided with asafety coating of for instance polypropylene to contain glass shardsthat may be formed on impact with a hard surface. Metal container bodiesare currently preferred as they are better able to withstand impact andare amenable to surface coating. Stainless steel, tinplate and aluminium(i.e. aluminium or aluminium alloy, including anodised aluminium)container bodies are especially suitable materials for this purpose,with aluminium being currently preferred as it is light and not readilybreakable.

Metal containers are typically lined or coated with an inert material toprotect the composition from reactions with the metal, therebypreventing or substantially eliminating any degradation of the activeingredients or other components of the composition.

Inert materials include any suitable polymer, lacquer, resin or othercoating treatment that creates a barrier between the container and thecomposition for preventing any chemical interaction between thecomposition and the container. Preferably the inert material is anon-metallic coating.

Known coatings for metal containers include acrylic, phenolic,polyester, epoxy and vinyl resins. However, a composition containing avitamin D derivative or analogue, is likely to be chemically degradedunder acidic conditions or in the presence of acidic reacting compounds.Moreover, corticosteroids are known to be chemically degraded underalkaline conditions or in the presence of alkaline reacting compounds.Accordingly, the container coating for use with a composition of thepresent invention should preferably be selected so that it exhibits noacidic or alkaline reactivity in itself, and that no acidic or alkalinereacting impurities are leached from it in the presence of thecomposition.

In the research leading to the present invention it was found, forexample, that a particular epoxyphenol resin inner lacquer wasincompatible with one of the active ingredients, causing unacceptablechemical degradation of calcipotriol. Such degradation may possibly bedue to the presence in the lacquer of colophonium which includes an acidgroup. On the other hand, the chemical stability of calcipotriol wassatisfactory when a polyimide-polyamide resin was used as the innercoating.

In addition to polyimide-polyamide coatings, other materials suitablefor lining the interior of the metal containers include polyamides,polyimides, polypropylene, polyethylene, fluoropolymers, includingperfluoroethylenepropylene copolymer (FEP), fluororubber (FPM),ethylene-propylene diene monomer rubber (EPDM), polytetrafluoroethylene(PTFE), ethylene tetrafluoroethylene copolymer (EFTE),perfluoroalkoxyalkanes, perfluoroalkoxyalkylenes, or blends offluoropolymers with non-fluorocarbon polymers. Fluoropolymers may, forexample, be used in combination with polyimide-polyamide resins.

The container coating material may be applied as a single layer, or inmultiple layers, for example allowing each layer to cure beforeapplication of a further layer. As well as shielding the compositionfrom the metal container, the application of more than one coating mayalso help prevent adhesion of the active ingredients on the containerwalls.

For the same reasons, valve components of the container that are broughtinto contact with the composition are also preferably made of, or coatedwith, materials that do not cause degradation of the composition. Forexample, metal valve components such as the valve cup may be coated withanodized silver, epoxymelamine or polypropylene.

As well as inhibiting leakage from the container, especially leakage ofpropellant, materials used for gaskets or seals within the containershould also preferably be chemically inert. For example, the containerbody and valve cup may be crimped together using an intermediate gasketwhich at least in part is exposed to contact with the composition, thusif the gasket is not made of inert material it may over time result indegradation of the composition.

Extensive testing of materials used for gaskets in conventional aerosolcontainer valves has established that polymeric materials prepared byvulcanization using sulphur-containing accelerators (e.g. thiazoles) arenot suitable as gasket materials for containers intended to include thepresent composition, probably due to reactivity of sulphur-containingresidues or impurities with one or both of the active ingredientsresulting in chemical degradation.

Similarly, gasket materials permeable to the propellants included in thepresent composition are not suitable as gasket materials for the presentpurpose.

Suitable gasket or seal materials for use with compositions accordingthe invention include fluoroelastomers (e.g. Viton V 600), fluorinatedethylene-propylene copolymer (FEP), fluororubber (FPM, e.g. VI500) orethylene-propylene diene monomer rubber (EPDM).

Suitable materials for the dip tube has been found to be e.g.polyethyleneand polypropylene. Suitable materials for the valve stem hasbeen found to be e.g. polyamide and acetal (POM).

In the embodiment shown in FIG. 6b , the composition comprises a vehiclephase (6), a propellant phase (7) and a vapor phase (8). In thisembodiment the spray container should be shaken thoroughly before use sothat the vehicle phase (6) will be homogenously suspended in thepropellant phase (7).

As shown in FIG. 7, the valve assembly may be composed of a valve cup(3), which is typically made of metal such as aluminium, attached to thecontainer body (1) by crimping, a valve body (5) which contains a valvestem (51) and a spring (53) connected to the actuator (4) which isdepressed for activation to expel the composition from the container.The valve stem (51) contains at least one aperture (52) with a diameterof 0.05-1 mm through which the composition present in the container mayflow when the actuator (4) is depressed. The valve stem aperture (52)may preferably be provided with a ball which allows the container to beused in different positions such as upside down or sideways.

The actuator (4) is provided with an insert (44) having a terminalorifice (41) with a diameter of 0.3-1.5 mm through which the compositionis expelled. The actuator (4) should be designed so as to provide anaerosol spray from the orifice (41) with droplets of a size sufficientlysmall to ensure a uniform spray of the product, yet sufficiently largeto ensure that the droplets of composition do not form a fine mist onexpulsion from the container such that droplets containing biologicallyactive substances may be accidentally inhaled.

The dimensions of the insert orifice (41) and valve stem aperture(s)(52) as well as the pressure within the container generally determinethe width of the spray cone formed when the composition is expelled fromthe aperture (4) and consequently the size of the area that will becovered by the sprayed composition.

In a particular embodiment, the container may be provided with means formetering a dose of the composition.

The invention is further illustrated by the following examples which arenot in any way intended to limit the scope of the invention as claimed.

EXAMPLES Example 1

Testing the Solubility of Calcipotriol and BDP in Different PropellantMixtures

2×12 100 ml glass bottles fitted with a valve and actuator were filledwith compositions containing 67 mg BDP, 13 mg calcipotriol, 20 g vehicle(comprising liquid paraffin, white soft paraffin and PPG-15-stearylether) and varying amounts of DME and butane as shown in Table 1. Thecomposition formed a continuous phase and a dispersed phase presumed tobe composed of long-chain alkanes (with 50 carbon atoms in the chain)present in the white soft paraffin. The dispersed phase sedimented inthe bottom portion of the composition on standing. Thus, the top portionof the composition contained only the continuous phase, while the bottomportion of the composition was composed of a mixture of continuous anddispersed phases.

TABLE 1 Sample DME (ml) Butane (ml) C1 6.7 40.0 C2 13.3 33.3 C3 20.026.7 C4 23.3 23.3 C5 1.3 45.3 C6 4.0 42.7 C7 30.0 16.7 C8 40.0 6.7 C946.7 0.0 D1 6.7 40.0 D2 13.3 33.3 D3 20.0 26.7 D4 23.3 23.3 D5 1.3 45.3D6 4.0 42.7 D7 30.0 16.7 D8 40.0 6.7 D9 46.7 0.0 C1-9 are samples takenfrom the continuous phase in the bottle D1-9 are samples taken from themixture of continuous and dispersed phases in the bottle

Before sampling the bottles were shaken vigorously until the contentsappeared to be homogenous after which the bottles were left overnight inthe dark resulting in sedimentation of the dispersed phase in the bottomportion of the bottle in admixture with the continuous phase. Sampleswere taken from the top and bottom portions of the composition through adip tube connected to the valve and reaching into the continuous phaseor mixed continuous-dispersed phase, such that the sample of eitherphase was sprayed into a brown glass. Care was taken not to shake thebottles while handling so that the diespersed phase remained sedimentedin the bottom portion of the composition. The sprayed samples wereplaced on a water bath at 40° C. for 5 hours until the propellant hadevaporated. The samples were then cooled for 1 hour at room temperature.

The amount of calcipotriol and BDP present in each sample was determinedby HPLC under the following operating conditions:

Column: Agilent Zorbas Eclipse Plus C18, 150×4.6 mm, 3.5 μm

Mobile phase: acetonitrile/methanol/0.01M (NH₄)₂HPO₄, pH 6.0, 25:45:30(v/v/v)

Flow: 1.2 ml/min.

Detection: 225-320 nM. Calculation at 264 nm for calcipotriol and 240 nmfor BDP

Column oven: 30° C.

Auto sampler: 20° C.

Run time: 30 min.

Injection: 80 μl

The results are shown in FIGS. 1a and 1b for calcipotriol and in FIGS.2a and 2b for BDP. It appears from the figures that calcipotriol and BDPare both completely dissolved at a ratio of butane to DME of 4:3 in boththe propellant and vehicle phases. Furthermore, it appears thatcalcipotriol and BDP are completely dissolved in 100% DME as thepropellant.

The physical stability of calcipotriol and BDP in the composition wasdetermined by polarized light microscopy. The results show that neithercalcipotriol or BDP recrystallize when the compositions are left tostand for 4 months.

Example 2

Vehicle Compositions

Compositions A-E

To prepare Compositions A-E, white soft paraffin was melted at 80° C.followed by cooling to 70° C. and maintaining that temperature.Calcipotriol monohydrate was dissolved in polyoxypropylene-15-stearylether to form a solution which was added to the molten paraffin withstirring. BDP was dispersed in liquid paraffin and the dispersion wasadded to the caclipotriol-containing paraffin mixture with stirring,after which the mixture was cooled to below 30° C. 30 g portions of themixture were transferred to aluminium spray containers provided with apolyamide-polyimide inner lacquer (HOBA 8460) after which a valve cupwas fastened to the container body by crimping. The requisite amount ofpropellant mixture was added through a tube, after which the containerwas shaken for 5 minutes for complete dissolution of the calcipotrioland BDP.

Composition A

Ingredients % w/w Calcipotriol monohydrate 0.002 Betamethasonedipropionate 0.026 Liquid paraffin 1.22 α-tocopherol 0.001PPG-15-stearyl ether 2.0 White soft paraffin 37.5 Dimethyl ether 31.7Butane 27.5Composition B

Ingredients % w/w Calcipotriol monohydrate 0.002 Betamethasonedipropionate 0.02 Liquid paraffin 0.9 α-tocopherol 0.001 PPG-15-stearylether 1.6 White soft paraffin 28.9 Dimethyl ether 36.7 Butane 31.9Composition C

Ingredients % w/w Calcipotriol monohydrate 0.001 Betamethasonedipropionate 0.006 Liquid paraffin 0.3 PPG-15-stearyl ether 0.5 Whitesoft paraffin 8.9 Dimethyl ether 90.3Composition D

Ingredients % w/w Calcipotriol monohydrate 0.002 Betamethasonedipropionate 0.030 Liquid paraffin 1.42 α-tocopherol 0.001PPG-15-stearyl ether 2.4 White soft paraffin 43.6 Dimethyl ether 52.6Composition E

Ingredients % w/w Calcipotriol monohydrate 0.002 Betamethasonedipropionate 0.026 Liquid paraffin 1.22 α-tocopherol 0.001PPG-15-stearyl ether 2.0 White soft paraffin 37.5 Dimethyl ether 27.5Butane 31.7Composition F

To prepare Composition F, hydrogenated castor oil is melted togetherwith liquid paraffin at 85-90° C. and cooled with homogenisation toabout 60° C. The mixture is then cooled to 25-30° C. with stirring. BDPis suspended in liquid paraffin and added to the homogenised mixture.Calcipotriol monohydrate is dissolved in polypropylene-15-stearyl etherand added to the mixture of the other ingredients, and the formulationwas homogenised to ensure a homogenous distribution of the activeingredients. 30 g portions of the mixture are transferred to aluminiumspray containers provided with a polyamide-polyimide inner lacquer (HOBA8460) after which a valve cup is fastened to the container body bycrimping. The requisite amount of propellant mixture is added through atube, after which the container is shaken for 5 minutes for completedissolution of the calcipotriol and BDP.

Composition F

Ingredients % w/w Calcipotriol monohydrate 0.002 Betamethasonedipropionate 0.03 PPG-15-stearyl ether 6.6 Hydrogenated castor oil 0.8Liquid paraffin 33.6 Dimethyl ether 27.3 Butane 31.7Compositions G and H

To prepare composition G, a solution of calcipotriol monohydrate inN-methylpyrrolidone is mixed with medium chain triglycerides andpolyoxypropylene-15-stearyl ether. Sonnecone DM1 and microcrystallinewax are melted at 80-85° C., and a solution of α-tocopherol in liquidparaffin is added at 80° C. with stirring until melting. After coolingto 70-75° C., the solvent mixture containing calcipotriol monohydrate isadded with stirring. After cooling to about 40° C., menthol is added andthe resulting mixture is stirred with cooling to below 30° C. 30 gportions of the mixture are transferred to aluminium spray containersprovided with a polyamide-polyimide inner lacquer (HOBA 8460) afterwhich a valve cup is fastened to the container body by crimping. Therequisite amount of propellant mixture is added through a tube, afterwhich the container is shaken for 5 minutes for complete dissolution ofthe calcipotriol and BDP.

Composition G

Ingredients % w/w Calcipotriol monohydrate 0.002 Betamethasonedipropionate 0.03 Medium chain triglycerides 2.5 N-methylpyrrolidone 1.0PPG-15-stearyl ether 0.6 Menthol 0.0025 Liquid paraffin 2.1 α-tocopherol0.0025 Petrolatum jelly white 30.3 (Sonnecone DM1) Microcrystalline wax4.1 (Multiwax 180 MH) Dimethyl ether 27.3 Butane 31.7

To prepare Composition H, white soft paraffin is melted at 80-85° C. andcooled to 70-75° C., and the solvent mixture is added with stirring. 30g portions of the mixture is transferred to aluminium spray containersprovided with a polyamide-polyimide inner lacquer (HOBA 8460) afterwhich a valve cup is fastened to the container body by crimping. Therequisite amount of propellant mixture is added through a tube, afterwhich the container is shaken for 5 minutes for complete dissolution ofthe calcipotriol and BDP.

Composition H

Ingredients % w/w Calcipotriol monohydrate 0.002 Betamethasonedipropionate 0.03 Medium chain triglycerides 2.5 N-methylpyrrolidone 1.0PPG-15-stearyl ether 0.6 White soft paraffin 36.5 Dimethyl ether 27.3Butane 31.7Compositions I-P

Compositions I is prepared by mixing the medium chain triglycerides,caprylic/capric glycerides and polyoxyl 40 hydrogenated castor oil andstirring the mixture for 15 min. at 50° C. with a magnetic stirrer. Thecalcipotriol monohydrate is dissolved in the mixture at 40° C. using amagnetic stirrer for 15 min. White soft paraffin is melted at 80° C. Thethree-component surfactant-solvent mixture containing calcipotriolmonohydrate is added to the melted paraffin and whisked until theointment mixture is homogenous. The homogenized mixture is cooled to 30°C. with stirring. Composition 3 is prepared in a similar fashion withthe exception that glycerol monooleate 40 is used as the co-surfactantinstead of caprylic/capric glycerides. 30 g portions of the mixture aretransferred to aluminium spray containers provided with apolyamide-polyimide inner lacquer (HOBA 8460) after which a valve cup isfastened to the container body by crimping. The requisite amount ofpropellant mixture is added through a tube, after which the container isshaken for 5 minutes for complete dissolution of the calcipotriol andBDP.

Ingredient (% w/w) Comp. I Comp. J calcipotriol monohydrate 0.002 0.002betamethasone dipropionate 0.03 0.03 medium chain triglycerides 1.1(Miglyol 812) long chain triglycerides (sesame 1.1 oil) caprylic/capricglycerides (Akoline 1.3 MCM) glycerol monooleate 40 (Peceol) 1.3polyoxyl 40 hydrogenated castor 1.8 1.8 oil (Cremophor RH 40) white softparaffin 31.2 31.2 dimethyl ether 36.2 36.2 butane 28.4 28.4

Compositions K-P are prepared in a similar fashion as composition I, butwith appropriate substitution of the surfactant, co-surfactant andsolvent as indicated in the table below.

Ingredient (% w/w) Comp. K Comp. L Comp. M Comp. N Comp. O Comp. Pcalcipotriol monohydrate 0.002 0.002 0.002 0.002 0.002 0.002betamethasone dipripionate 0.03 0.03 0.03 0.03 0.03 0.03 lauroylmacrogol-6-glycerides 3.4 5.1 5.7 4.5 4.5 4.5 (Labrafil M2130 CS)polyglyceryl-3-diisostearate 3.4 (Plurol Diisostearique) linoleylmacrogol-6-glyceride 1.7 (Labrafil M2125CS) diethylene glycol monoethyl1.1 ether (Transcutol P) propylene glycol monolaurate 2.3 (Lauroglycol90) propylene glycol 2.3 monocaprylate (Capryol 90) propylene glycol 2.3monocaprylate (Capryol 90) glycerol monocaprylocaprate 0.4 0.4 0.4 0.40.4 0.4 (IMWITOR 742) white soft paraffin 30 30 30 30 30 30 dimethylether 34.3 34.3 34.3 34.3 34.3 34.3 butane 28.5 28.5 28.5 28.5 28.5 28.5

Example 3

Chemical Stability of Calcipotriol and BDP in Different Compositions

Composition E prepared as described in Example 2 above was stored in thespray containers for 3 months at 40° C. Samples of the composition weretaken at 1, 2 and 3 months of storage, respectively, and the content ofcalcipotriol and BDP as well as possible degradation products (relatedimpurities) was determined by HPLC. The results are shown in the Tablebelow in percent of the theoretical initial value.

calcipotriol betamethasone dipropionate % of initial % of initialSampling time (theoretical) % impurities (theoretical) % impuritiesInitial analysis 99.3 0.7 97.2 0.2 1 month 95.1 2.0 95.6 0.2 2 months92.6 1.0 96.3 0.3 3 months 93.6 1.9 96.7 0.5

It appears from the results that there is a discrepancy between the lossof calcipotriol after 3 months at 40° C. and the amount of impuritiesdetermined. This suggests that the apparent loss of calcipotriol is notthe result of degradation of calcipotriol during storage, but may beascribed to other causes such as, for instance, adsorption ofcalcipotriol to one or more of the container components, possibly thedip tube or inner lacquer. We have therefore concluded that both activeingredients are chemically stable under the stated conditions,suggesting that the composition may have a shelf life of about 2 yearsat 25° C.

Example 4

Penetration Studies

To investigate the skin penetration and permeation of calcipotriol fromcompositions of the invention, a skin diffusion experiment wasconducted. Full thickness skin from pig ears was used in the study. Theears were kept frozen at −18° C. before use. On the day prior to theexperiment the ears were placed in a refrigerator (5±3° C.) for slowdefrosting. On the day of the experiment, the hairs were removed using aveterinary hair trimmer. The skin was cleaned of subcutaneous fat usinga scalpel and two pieces of skin were cut from each ear and mounted onFranz diffusion cells in a balanced order.

Static Franz-type diffusion cells with an available diffusion area of3.14 cm² and receptor volumes ranging from 8.6 to 11.1 ml were used insubstantially the manner described by T. J. Franz, “The finite dosetechnique as a valid in vitro model for the study of percutaneousabsorption in man”, in Current Problems in Dermatology, 1978, J. W. H.Mall (Ed.), Karger, Basel, pp. 58-68. The specific volume was measuredand registered for each cell. A magnetic bar was placed in the receptorcompartment of each cell. After mounting the skin, physiological saline(35° C.) was filled into each receptor chamber for hydration of theskin. The cells were placed in a thermally controlled water bath whichwas placed on a magnetic stirrer set at 400 rpm. The circulating waterin the water baths was kept at 35±1° C. resulting in a temperature ofabout 32° C. on the skin surface. After one hour the saline was replacedby receptor medium, 0.04 M isotonic phosphate buffer, pH 7.4 (35° C.),containing 4% bovine serum albumin. Sink conditions were maintained atall times during the period of the study, i.e. the concentration of theactive compounds in the receptor medium was below 10% of the solubilityof the compounds in the medium.

The in vitro skin permeation of each test composition was tested in 6replicates (i.e. n=6). Each test composition was sprayed onto the skinmembrane at 0 hours. A glass spatula was used to spread the compositionevenly over the skin surface.

The skin penetration experiment was allowed to proceed for 21 hours.Samples were then collected from the following compartments at 2, 6 and21 h:

The stratum corneum was collected by tape stripping 10 times usingD-Squanne® tape (diameter 22 mm, CuDerm Corp., Dallas, Tex., USA). Eachtape strip is applied to the test area using a standard pressure for 5seconds and removed from the test area in one gentle, continuous move.For each repeated strip, the direction of tearing off was varied. Theviable epidermis and dermis was then sampled from the skin in a similarfashion.

Samples (1 ml) of the receptor fluid remaining in the diffusion cellwere collected and analysed.

The concentration of calcipotriol in the samples were determined by LCmass spectrometry.

The results appear from FIGS. 3 and 4 below which show the amount ofcalcipotriol and BDP, respectively, found in viable skin (dermis andepidermis) and receptor fluid in % of the applied dose 2, 6 and 21 hoursafter application. The results show that application of Composition Eleads to a significant increase in skin permeation of calcipotriol andBDP compared to Daivobet® ointment.

Example 5

Biological Activity of the Compositions

As shown in FIG. 5 below, cathelicidin is an antimicrobial peptideexpressed in human keratinocytes. The expression of cathelicidin isstrongly induced on infection of the skin or disruption of the skinbarrier. In psoriasis, the level of cathelicidin is increased inlesional skin of psoriasis patients. It has been found that theexpression of the gene encoding cathelicidin may be induced by vitaminD₃ or vitamin D analogues such as calcipotriol (cf. T T Wang et al, J.Immunol. 173(5), 2004, pp. 2909-2912; J Schauber et al., Immunology118(4), 2006, pp. 509-519; Schauber and Gallo, J. Allergy Gin Immunol122, 2008, pp. 261-266; M. Peric et al., PloS One 4(7), Jul. 22, 2009,e6340) through binding to the vitamin D receptor. This finding has beenutilized to develop an assay in which the uptake and biological activityof calcipotriol in human keratinocytes from the tested compositions hasbeen determined by measuring the level of induction of the gene encodingcathelicidin.

In the assay, Composition E prepared as described in Example 2 above wassprayed topically in triplicate on reconstructed human epidermisconsisting of normal human keratinocytes cultured for 12 days on 0.5 cm²polycarbonate filters (available from SkinEthic® Laboratories, Nice,France). The tissue was treated for two days followed by separation ofthe epidermis from the polycarbonate filter and snap-frozen in liquidnitrogen. RNA was extracted from the cells and cDNA synthesized byconventional procedures. Quantitative real-time PCR (qPCR) was thenperformed using the following assays from Applied Biosystems: CAMPHs0018038_m1 and GAPDH Hs99999905_m1. The expression levels ofcathelicidin were normalized to GAPDH and a relative quantification wasmade by comparison with Daivobet® ointment.

The results show a 2.3 fold increase in the biological activation ofcathelicidin relative to that obtained with Daivobet® ointment.

Example 6

Chemical Stability of Calcipotriol/BDP in the Presence of DifferentInner Lacquers

Batches of Composition A prepared as described in Example 2 and placedin aluminium spray containers provided with two different types of innerlacquer, an epoxyphenol based lacquer (HOBA 7940/7407) and apolyimide-polyamide based lacquer (HOBA 8460), respectively, were testedfor chemical stability of the active ingredients after standing for 1month at 40° C. by spraying samples of each batch into a glass andsubjecting them to HPLC by the procedure described in Example 3.

The results are shown in the table below.

Calcipotriol Batch Calcipotriol 1 m/40° C. BDP (mg/g) BDP (mg/g) #Lacquer initial (μg/g) (μg/g) initial 1 m/40° C. 1 EP 48.7 24.5 0.6260.606 2 PI-PA 50.8 48.6 0.632 0.623 3 EP 46.7 32.4 0.609 0.605 4 PI-PA49.6 48.8 0.623 0.624 5 EP 48.4 23.5 0.610 0.603 6 PI-PA 50.2 48.7 0.6270.625 7 EP 47.0 32.5 0.603 0.602 8 PI-PA 49.8 48.3 0.626 0.618 9 EP 47.827.6 0.611 0.602 10 PI-PA 49.3 48.1 0.619 0.617 11 EP 44.7 35.6 0.6000.601 12 PI-PA 48.9 48.4 0.617 0.616 EP: epoxyphenol based lacquerPI-PA: polyimide-polyamide based lacquer

It appears from the table that calcipotriol is unacceptably degradedwhen an epoxyphenol based lacquer is used as the inner lacquer of thespray container, while the chemical stability is acceptable in thepresence of a polyimide-polyamide based inner lacquer. The chemicalstability of betamethasone dipropionate appears to be much less affectedby the composition of these inner lacquers. It is assumed that thedegradation of calcipotriol shown in the table is caused by one or moreacid reacting components in the epoxyphenol based HOBA 7940/7407 lacquerthat may be leached from the lacquer due to the solvent action of thepropellant mixture. It is currently assumed that such a component iscolophonium as it includes an acid group.

Example 7

Testing the Solubility of Vitamin D Analogues and Corticosteroids inDifferent Propellant Mixtures

100 ml glass bottles fitted with a valve and actuator were filled with acompositions containing API (10 mg of calcitriol, tacalcitol,maxacalcitol, 30 mg clobetasol propionate, 60 mg betamethasone17-valerate, hydrocortisone 17-butyrate, 120 mg hydrocortisone valerateor 800 mg hydrocortisone) and varying amounts of DME and butane (46.7 mlbutane, 6.7 ml DME and 40.0 ml butane, or 23.3 ml DME and 23.3 mlbutane). Before sampling the bottles were shaken vigorously until thecontents appeared to be homogenous after which the bottles were leftovernight in the dark resulting in sedimentation of the undissolved API.Samples were taken from the top of the composition through a dip tubeconnected to the valve, by spraying the sample into a scintillationglass. Care was taken not to shake the bottles while handling so thatthe undissolved API remained sedimented in the bottom portion of thecomposition. The API in the glass was dissolved in solvent forextraction and diluted if necessary before injected into the HPLC.

The amount of calcitriol, tacalcitol, maxacalcitol, betamethasone17-valerate and clobetasol propionate present in each sample wasdetermined by HPLC under the following operating conditions:

Column: 4.6×150 mm Waters Sunfire C18. 3.5 μm column

Mobile phase: Acetonitrile-methanol-water (20:50:30)

Flow: 1.2 ml/min.

Detection: PDA 210 nm-350 nm

-   -   Calculation for betamethasone 17-valerate and clobetasol        propionate is done at 240 nm    -   Calculation for vitamin D analogues is done at 260 nm        Column oven: 35° C.        Auto sampler: 20° C.        Run time: 40 min.        Injection: Variable according to standard curve for each API        Retention time: 6.2 minutes (clobetasol propionate)    -   6.7 minutes (betamethasone 17-valerate)    -   10.5 minutes (maxacalcitol)    -   28.6 minutes (calcitriol)    -   32.6 minutes (tacacalcitol)

The amount of hydrocortosone, hydrocorticone-valerate andhyrdrocortisone 17-butyrate present in each sample was determined byHPLC under the following operating conditions:

Column: Phenomenex Precolumn C18 4.0 mm×2.0 mm or equivalent+Waters

-   -   Sunfire C18 3.5 μm, 100 mm×4.6 mm or equivalent        Mobile phase: Eluent A: Tetrahydrofuran    -   Eluent B: Water        Gradient:

Time (min.) Eluent A (%) Eluent B (%) Curve (Empower) 0.0 23 77 — 6.0 2377 11  15.5 50 50 6 23.0 23 77 1Flow: 1.0 ml/min.Pre column volume: Corresponding to the size of the loopDetection: UV-254 nm

-   -   PDA-detector 220-320 nm        Injection: Variable according to standard curve for each API        Column oven: 40° C.        Auto sampler: Ambient        Runtime: Minimum 4 times the retention time for hydrocortisone        Retention time: 6.0 minutes (hydrocortisone)    -   12.7 minutes (hydrocortisone 17-butyrate)    -   14.5 minutes (hydrocortisone valerate)

The results are shown in Table a and Table b for vitamin D analogues andcorticosteroids, respectively. It appears from the Tables that thesolubility of vitamin D analogues and corticosteroids increases byincreasing the DME amount.

TABLE a Solubility of vitamin D analogues at ambient temperature. Valuesare mean values from 2 determinations from the same bottle. DME inpercent of solubility (μg/g propellant) total propellant (weight %)calcitriol tacalcitol maxacalcitol 0 14 24 32 16 >250 >250 >30053 >250 >250 >300

TABLE b Solubility of corticosteroids at ambient temperature. Values aremean values from 2 determinations from the same bottle. DME in % (byweight) Solubility (μg/g propellant) of total Betamethasone- ClobetasolHydrocortisone Hydrocortisone propellant 17-valerate propionate17-butyrate valerate Hydrocortisone 0 3 5 3 9 5 16 73 133 68 154 853 >1900 >800 >1600 >3200 241

Example 8

Chemical Stability of Calcipotriol/BDP in the Presence of DifferentGasket Materials

In order to test the compatibility of the composition with variousgasket materials, samples were prepared with Composition E, see Example2, filled in aluminum spray containers with a polyamide-polyimide innerlacquer and closed with a valve cup crimped to the container body. Toeach container, 10 pieces or an equivalent amount of gasket testmaterial were added to the spray container and allowed to be submergedin the composition. The containers were stored at 25° C. or 40° C. andtested after 1 and 3 months at 40° C., and after 3 months at 25° C.

After storage, the composition was sprayed out in a glass bottle, andthe propellants were allowed to evaporate for 2 days. The non-volatilepart of the composition was analyzed for calcipotriol, betamethasonedipropionate and their related organic impurities.

The amount of calcipotriol was determined by HPLC after liquidextraction followed by a controlled isomerization at 50° C. Methyltestosterone was used as the internal standard. The following conditionswere used for the HPLC analysis:

Column: LiChrospher RP-18, 125×4 mm, 5 μm

Mobile phase: Acetonitrile/methanol/0.01M (NH₄)₂PO₄ (20:50:30)

Flow: 2.0 ml/min

Detection: UV-264 nm

Injection: 50 μl

Run time: Approx. 9 minutes

The organic impurities related to calcipotriol were determined by HPLCafter liquid extraction, using the following conditions:

Column: YMC ODS-AM, 150×4.6 mm, 3 μm

Mobile phase: Acetonitrile/methanol/0.01M (NH₄)₂PO₄ (20:50:30)

Flow: 1.0 ml/min

Detection: UV-264 nm

Injection: 500 μl

Run time: 2 times the retention time of calcipotriol

The amount of betamethasone dipropionate was determined by HPLC afterliquid extraction, using beclomethasone dipropionate as internalstandard and the following HPLC conditions:

Column: Superspher RP-18, 75×4 mm, 4 μm

Mobile phase: Acetonitrile/water (50:55)

Flow: 1.5 ml/min

Detection: UV-240 nm

Injection: 20 μl

Run time: Approx. 9 minutes

The organic impurities related to betamethasone dipropionate wereextracted by liquid extraction and analyzed by HPLC using the followingconditions:

Column: LiChrospher RP-18, 125×4 mm, 5 μm

Mobile phase: Acetonitrile/0.05M (NH₄)₂PO₄ pH 7 (50:55)

Flow: 2.0 ml/min

Detection: UV-240 nm

Injection: 20 μl

Run time: Approx. 20 minutes

The results are presented in the table below:

BDP 5,6-Trans- 24-Epi- Gasket Temp/ Calcipotriol (mg/ calcipotriolcalcipotriol type months (μg/g) g) (area-%) (area-%) Buna 40° C./1 m40.2 0.557 4.3 0.9 40° C./3 m 27.3 0.555 6.3 1.3 25° C./3 m 42.5 0.5592.6 0.8 Viton 40° C./1 m 48.9 0.610 0.4 0.6 40° C./3 m 48.7 0.607 0.60.6 25° C./3 m 49.8 0.607 0.2 0.5 NPR 40° C./1 m 44.1 0.554 0.3 4.7 40°C./3 m 38.4 0.549 0.3 9.6 25° C./3 m 46.6 0.535 0.1 2.9 EPDM 40° C./1 m49.2 0.641 0.5 0.7 40° C./3 m 47.6 0.611 1.0 0.9 25° C./3 m 49.5 0.6160.4 0.8 Buna and NPR are nitrile rubbers, Viton is a fluoroelastomer,and EPDM is a ethylene-propylene diene monomer rubber.

The data show that two of the gasket types, Buna and NPR, resulted indecomposition of both calcipotriol and betamethasone dipropionate. Basedon this compatibility test, it was concluded that these two materialswere not suitable for use in contact with the tested composition. TheViton and EPDM gaskets did not have negative impact on the stability ofcalcipotriol and betamethasone dipropionate and they are thereforeconsidered to be useful as gasket materials for the composition tested.

The invention claimed is:
 1. A sprayable, storage stable, substantiallyanhydrous topical composition comprising a therapeutically effectiveamount of calcipotriol or calcipotriol monohydrate and a therapeuticallyeffective amount of betamethasone dipropionate, wherein the calcipotriolor calcipotriol monohydrate and the betamethasone dipropionate aredissolved in a pharmaceutically acceptable propellant comprising atleast one of dimethyl ether or methylethyl ether, or propellant mixturecomprising a first propellant comprising at least one of dimethyl etheror methylethyl ether and a second propellant comprising at least one ofa C₃₋₅ alkane, hydrofluoroalkane, hydrochloroalkane, fluoroalkane orchlorofluoroalkane, the composition further comprises a pharmaceuticallyacceptable lipid carrier solubilized or suspended in said propellant orpropellant mixture, the lipid carrier comprises one or more paraffinswherein said lipid carrier upon application on skin and evaporation ofthe propellant or propellant mixture forms a semi-solid and occlusivelayer at the site of application, the composition optionally comprisesnon-evaporating oily co-solvent, and wherein a supersaturated solutionof the calcipotriol or calcipotriol monohydrate and the betamethasonedipropionate is formed on the skin after application of the compositionand evaporation of the propellant or propellant mixture.
 2. Thecomposition according to claim 1, wherein the propellant is present inan amount from 45-95% w/w.
 3. The composition according to claim 2,wherein the propellant is present in an amount from 50-90% w/w.
 4. Thecomposition according to claim 3, wherein the propellant is present inan amount from 55-70% w/w.
 5. The composition according to claim 1,wherein the propellant is a mixture of dimethylether and C₃₋₅ alkane. 6.The composition according to claim 5, wherein the C₃₋₅ alkane isn-propane, isopropane, n-butane and/or isobutane.
 7. The compositionaccording to claim 6, wherein the C₃₋₅ alkane is n-butane and/orisobutane.
 8. The composition according to claim 7, wherein the C₃₋₅alkane is n-butane.
 9. The composition according to claim 7, wherein theratio of n-butane and/or isobutane to dimethyl ether is in the range of6:1-0:1 v/v.
 10. The composition of claim 7, wherein the ratio ofn-butane and/or isobutane to dimethyl ether is in the range of 5:1-1:2v/v.
 11. The composition of claim 7, wherein the ratio of n-butaneand/or isobutane to dimethyl ether is in the range of 4:1-1:1 v/v. 12.The composition of claim 7, wherein the ratio of n-butane and/orisobutane to dimethyl ether is in the range of 4:2-4:3 v/v.
 13. Thecomposition of claim 7, wherein the ratio of n-butane and/or isobutaneto dimethyl ether is in the range of 4:3-1:1 v/v.
 14. A compositionaccording to claim 1, comprising (a) about 0.00001-0.05% w/wcalcipotriol or calcipotriol monohydrate, (b) about 0.0005-1% w/wbetamethasone dipropionate, (c) about 5-55% w/w of the lipid carrier,and (d) about 45-95% w/w of the propellant.
 15. The compositionaccording to claim 1, wherein the amount of calcipotriol or calcipotriolmonohydrate is 0.00001-0.05% w/w of the composition.
 16. The compositionaccording to claim 15, wherein the amount of calcipotriol orcalcipotriol monohydrate is 0.001 or 0.002% w/w of the composition. 17.The composition according to claim 1, wherein the amount ofbetamethasone dipropionate is 0.0005-1% w/w of the composition.
 18. Thecomposition according to claim 17, wherein the amount of betamethasonedipropionate is 0.006, 0.02, 0.026 or 0.03% w/w of the composition. 19.The composition according to claim 1, wherein the amount ofbetamethasone dipropionate is 0.026% w/w and the amount of calcipotriolmonohydrate is 0.002% w/w or the corresponding amount of calcipotriol.20. The composition according to claim 1, further comprising anon-evaporating oily co-solvent selected from at least one of thefollowing solvent classes (a) a compound of general formula IH(OCH₂C(CH₃)H)_(x)OR¹ wherein R¹ is straight or branched chain C₁₋₂₀alkyl, and x is an integer of 2-60; (b) an isopropyl ester of a straightor branched chain C₁₀₋₁₈ alkanoic or alkenoic acid; (c) a propyleneglycol diester of a C₈₋₁₄ alkanoic or alkenoic acid; (d) a straight orbranched C₈₋₂₄ alkanol or alkenol; (e) highly purified vegetable oilssuch as medium chain triglycerides or long chain triglycerides; and (f)N-alkylpyrrolidone or N-alkylpiperidone.
 21. The composition accordingto claim 20, wherein the compound of general formula I ispolyoxypropylene-15-stearyl ether, polyoxypropylene-11-stearyl ether,polyoxypropylene-14-butyl ether, polyoxypropylene-10-cetyl ether orpolyoxypropylene-3-myristyl ether.
 22. The composition according toclaim 20, wherein the isopropyl ester of a straight or branched chainC₁₀₋₁₈ alkanoic or alkenoic acid is isopropyl myristate, isopropylpalmitate, isopropyl isostearate, isopropyl linolate or isopropylmonooleate.
 23. The composition according to claim 20, wherein thepropylene glycol diester of a C₈₋₁₄ alkanoic acid is propylene glycoldipelargonate.
 24. The composition according to claim 20, wherein thestraight C₈₋₂₄ alkanol or alkenol is capryl, lauryl, cetyl, stearyl,oleyl, linoelyl or myristyl alcohol, or wherein the branched C₈₋₂₄alkanol is a branched C₁₈₋₂₄ alkanol.
 25. The composition according toclaim 20, wherein the N-alkylpyrrolidone is N-methylpyrrolidone.
 26. Thecomposition according to claim 1, comprising 10-50% w/w of the lipidcarrier.
 27. The composition according to claim 26, comprising 15-45%w/w of the lipid carrier.
 28. The composition according to claim 27,comprising 20-40% w/w of the lipid carrier.
 29. The compositionaccording to claim 1, wherein the paraffin is selected from paraffinsconsisting of hydrocarbons with chain lengths from C₅ to C₆₀, the chainlengths peaking at C₁₄₋₁₆, C₁₈₋₂₂, C₂₀₋₂₂, C₂₀₋₂₆, C₂₈₋₄₀, and C₄₀₋₄₄(as determined by gas chromatography).
 30. The composition according toclaim 29, further comprising a lipophilic viscosity-increasing agentcapable of imparting to the lipid carrier the property of forming asemi-solid and occlusive layer on skin on application and evaporation ofthe propellant, said viscosity-increasing agent being selected from thegroup consisting of microcrystalline wax, silicone wax and hydrogenatedcastor oil, or mixtures thereof, and an isoparaffin.
 31. The compositionaccording to claim 1, comprising 0.1-10% w/w of the oily co-solvent. 32.The composition of claim 31, comprising 1-2.5% w/w or 1.5-2% w/w of theoily co-solvent.
 33. The composition according to claim 20, wherein theoily co-solvent is medium chain triglycerides.
 34. The compositionaccording to claim 22, wherein the isopropyl ester of a straight orbranched chain C₁₀₋₁₈ alkanoic or alkenoic acid is isopropyl myristate.35. The composition according to claim 24, wherein the straight C₈₋₂₄alkanol or alkenol is oleyl alcohol.
 36. The composition according toclaim 1, wherein the amount of calcipotriol in said composition withoutthe propellant corresponds to about 0.005% w/w calcipotriol and theamount of betamethasone dipropionate in the composition without thepropellant is about 0.064% w/w.
 37. The composition according to claim1, wherein the amount of calcipotriol in said composition without thepropellant corresponds to about 0.005 w/w calcipotriol and the amount ofbetamethasone dipropionate in the composition without the propellant isabout 0.064% w/w and wherein the propellant is a mixture of dimethylether and one or more C₃₋₅ alkanes.
 38. The composition according toclaim 1, wherein the amount of calcipotriol in the composition withoutthe propellant corresponds to about 0.005% w/w calcipotriol and theamount of betamethasone dipropionate in the composition without thepropellant is about 0.064% w/w and wherein the propellant is a mixtureof n-butane and/or isobutane and dimethyl ether and wherein the ratio ofn-butane and/or isobutane to dimethyl ether is in the range of 6:1-0:1v/v.
 39. The composition of claim 38, wherein the propellant is amixture of n-butane or isobutane and dimethyl ether and the ratio ofn-butane and/or isobutane to dimethyl ether is in the range of 5:1-1:2v/v.
 40. The composition of claim 39, wherein the ratio of n-butaneand/or isobutane to dimethyl ether is in the range of 4:1-1:1 v/v. 41.The composition of claim 39, wherein the ratio of n-butane and/orisobutane to dimethyl ether is in the range of 4:2-1:1 v/v.
 42. Thecomposition of claim 39, wherein the ratio of n-butane and/or isobutaneto dimethyl ether is in the range of 4:2-4:3 v/v.
 43. The composition ofclaim 39, wherein the ratio of n-butane and/or isobutane to dimethylether is in the range of 4:3-1:1 v/v.
 44. The composition according toany one of claims 36 to 43, wherein the propellant consists of a mixtureof dimethyl ether and n-butane.
 45. The composition according to any oneof claims 36 to 43, wherein the amount of propellant is 45-95% w/w. 46.The composition of claim 45 wherein the amount of propellant is 45-90w/w.
 47. The composition of claim 45 wherein the amount of propellant is45-70% w/w.
 48. The composition of claim 45 wherein the amount ofpropellant is 50-70 w/w.
 49. The composition according to claim 1,wherein the amount of calcipotriol in the composition without thepropellant corresponds to about 0.005% w/w calcipotriol and the amountof betamethasone dipropionate in the composition without the propellantis about 0.064% w/w and wherein the lipid carrier which upon applicationon the skin and evaporation of the propellant form a semi-solid andocclusive layer at the site of application comprises petrolatum andliquid paraffin.
 50. The composition according to claim 1, wherein theamount of calcipotriol in the composition without the propellantcorresponds to about 0.005% w/w calcipotriol and the amount ofbetamethasone dipropionate in the composition without the propellant isabout 0.064% w/w and wherein the propellant is a mixture of dimethylether and one or more C₃₋₅ alkanes and wherein the lipid carrier whichupon application on the skin and evaporation of the propellant form asemi-solid and occlusive layer at the site of application comprisespetrolatum and liquid paraffin.
 51. The composition according to claim1, wherein the amount of calcipotriol in the composition without thepropellant corresponds to about 0.005 w/w calcipotriol and the amount ofbetamethasone dipropionate in the composition without the propellant isabout 0.064% w/w, wherein the propellant is a mixture of n-butane and/orisobutane and dimethyl ether where the ratio of n-butane and/orisobutane to dimethyl ether is in the range of 6:1-0:1 v/v and whereinthe lipid carrier which upon application on the skin and evaporation ofthe propellant form a semi-solid and occlusive layer at the site ofapplication comprises petrolatum and liquid paraffin.
 52. Thecomposition of claim 51, wherein the propellant is a mixture of n-butaneand/or isobutane and dimethyl ether and the ratio of n-butane and/orisobutane to dimethyl ether is in the range of 5:1-1:2 v/v.
 53. Thecomposition of claim 51, wherein the ratio of n-butane and/or isobutaneto dimethyl ether is in the range of 4:1-1:1 v/v.
 54. The composition ofclaim 51, wherein the ratio of n-butane and/or isobutane to dimethylether is in the range of 4:2-1:1 v/v.
 55. The composition of claim 51,wherein the ratio of n-butane and/or isobutane to dimethyl ether is inthe range of 4:2-4:3 v/v.
 56. The composition of claim 51, wherein theratio of n-butane and/or isobutane to dimethyl ether is in the range of4:3-1:1 v/v.
 57. The composition of any one of claims 49 to 56, whereinthe propellant consists of dimethyl ether and n-butane.
 58. Thecomposition of any one of claims 49 to 56, wherein the amount ofpropellant is 45-95% w/w.
 59. The composition of claim 58 wherein theamount of propellant is 45-90% w/w.
 60. The composition of claim 59wherein the amount of propellant is 45-70% w/w.
 61. The composition ofclaim 60 wherein the amount of propellant is 50-70 w/w.
 62. Thecomposition of claim 1 wherein the amount of calcipotriol in thecomposition without the propellant corresponds to about 0.005% w/wcalcipotriol and the amount of betamethasone dipropionate in thecomposition without the propellant is about 0.064% betamethasone w/w andwherein propellant is a mixture of dimethyl ether and one or more C₃₋₅alkanes and the amount of propellant is 45-70% w/w.
 63. The compositionof claim 62 wherein the propellant is a mixture of n-butane and/orisobutane, and dimethyl ether; and the ratio of n-butane and/orisobutane to dimethyl ether is in the range of 4:2-4:3 v/v.
 64. Thecomposition of claim 62 wherein the propellant is a mixture of n-butaneand/or isobutane, and dimethyl ether; and the ratio of n-butane and/orisobutane to dimethyl ether is in the range of 4:3-1:1 v/v.
 65. Thecomposition according to claim 62, wherein the lipid carrier comprisespetrolatum and liquid paraffin.
 66. The composition according to claim 2wherein the amount of propellant is 45-70% w/w.
 67. The compositionaccording to claim 1, wherein the propellant is a mixture ofdimethylether and one or more C₃₋₅ alkanes, and the lipid carrierconsists essentially of petrolatum and liquid paraffin.